title: The TNF family member 4-1BBL sustains inflammation by interacting with TLR signaling components during late-phase activation.
abstract: Activation of Toll-like receptor (TLR)-dependent signaling leads to the expression of genes encoding proinflammatory factors, such as tumor necrosis factor-α (TNF-α), and this proinflammatory gene expression is sustained for the duration of the inflammatory response. TLR4-mediated inflammation, which occurs in two phases, depends on the TNF family member 4-1BB ligand (4-1BBL) to sustain TNF-α production during late-phase signaling. We showed that Toll-interleukin-1 receptor (TIR) domain-containing adaptor protein (TIRAP) and the kinase IRAK2 interacted with 4-1BBL to mediate late-phase TLR4 signaling. Expression of 4-1bbl depended on early TLR4 signaling that also induced Tnf expression, and 4-1BBL translocated to the plasma membrane, where it interacted with TLR4 to mediate late-phase signaling. TLR4-4-1BBL-mediated signaling depended on TIRAP and IRAK2, as well as a complex consisting of the E3 ubiquitin ligase TRAF6 (TNF receptor-associated factor 6), the kinase TAK1 (transforming growth factor-β-activated kinase 1), and the adaptor protein TAB1 (TAK-binding protein 1). Inhibition of this late-phase pathway reduced the extent of TNF-α production by mouse macrophages exposed to the TLR4 ligand lipopolysaccharide (LPS) and ameliorated LPS-induced sepsis in mice. Together, these data suggest that TIRAP and IRAK2 are critical for the sustained inflammatory response that is mediated by late-phase signaling by the TLR-4-1BBL complex.
authors.affiliation: 1Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Ma
authors.forename: Bo-Ram
authors.initials: BR
authors.lastname: Bang
authors.forename: Jiawei
authors.initials: J
authors.lastname: Lu
authors.forename: So-Young
authors.initials: SY
authors.lastname: Eun
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Otsuka
authors.forename: Michael
authors.initials: M
authors.lastname: Croft
authors.forename: Peter
authors.initials: P
authors.lastname: Tobias
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Kang
mesh_terms: D053330:4-1BB Ligand / Q000235:genetics / Q000276:immunology*; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D021381:Protein Transport / Q000235:genetics / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology; D018805:Sepsis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D053330:4-1BB Ligand; D053592:Interleukin-1 Receptor-Associated Kinases; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D008562:Membrane Glycoproteins; D017472:Receptors, Interleukin-1; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C434984:TIRAP protein, human; C499045:TIRAP protein, mouse; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse